Sign up to receive free email alerts when patent applications with chosen keywords are publishedSIGN UP

Abstract:

The present invention provides a method for the N-demethylation and/or
N-acylation of an N-methylated heterocycle such as morphine alkaloids or
tropane alkaloids. The method comprises reacting the heterocycle with an
acylating agent in the presence of a metal catalyst.

Claims:

1. A one pot method for the N-demethylation and N-acylation of a tertiary
N-methylated heterocycle comprising reacting a N-methylated heterocycle
substrate with an acylating agent reactant in the presence of a catalyst
to obtain a morphine derivative product.

2. A method according to claim 1 wherein the N-methylated heterocyle
substrate selected from the group consisting of compounds (I), (II) and
(III): ##STR00020## wherein E is H, CH3, COR, or COOR; G is O, OH,
OR, OCR, or OCOR; and J is OH, OR, OCR, or OCOR.

3. The method according to claim 1, wherein the N-methylated heterocycle
is selected from the group consisting of a morphine alkaloid, a tropane
alkaloid and derivatives thereof.

4. The method according to claim 3, wherein the morphine alkaloid is
selected from the group consisting of thebaine, oripavine,
14-hydroxycodeinone, 14-hydroxymorphinone, morphine, codeine,
hydromorphone, hydrocodone, oxymorphone, oxycodone, hydromorphol and
oxymorphol.

5. The method according to claim 4, wherein the morphine alkaloid is
hydrocodone.

6. The method according to claim 4, wherein the tropane alkaloid and
derivatives thereof is selected from the group consisting of tropinone,
tropane, tropine, atropine, cocaine and other bicyclo-[3.2.1]-azabicyclic
methylamines.

25. The method according to claim 24, wherein the catalyst is selected
from the group consisting of Cu, Fe, Ru, Co, Rh, Ir, Ni, Pd, Pt, Ge, and
Sn.

26. The method according to claim 24, wherein the catalyst is selected
from the group consisting of Os, Cu, Ag, Au, and Pb.

27. The method according to claim 26, wherein the catalyst is a palladium
catalyst selected from the group consisting of Pd, Pd(OAc)2,
PdCl2, PdCl2(PPh3)4, PdBr2, Pd(acac)2,
Pd2(dba)3, Pd(dba)2, and Pd(PPh3).sub.4.

28. The method according to claim 27, wherein the palladium catalyst is
Pd(OAc).sub.2.

29. The method according to claim 1, wherein the catalyst is present in
the range of from about 0.01 equivalents to 1.2 equivalents.

30. The method according to claim 29, wherein the catalyst is present in
the range of from about 0.01 equivalents to 0.5 equivalents.

31. The method according to claim 29, wherein the catalyst is present in
about 0.2 equivalents.

32. The method according to claim 1, wherein the reaction takes place in
the presence of at least one solvent.

33. The method according to claim 32 wherein the solvent is selected from
the group consisting of water, benzene, dioxane, toluene, lower (C1-C4)
alcohols and mixtures thereof.

34. The method according to claim 33, wherein the at least one solvent is
dioxane.

36. A norhydrocodone derivative obtained according to the method of claim
1.

37. A norhydrocodone derivative according to claim 36, comprising a
structure selected from the group below: ##STR00026##

38. A derivative according to claim 37 wherein R is CH.sub.3.

39. A derivative according to claim 37 wherein R is CH(CH3)2

40. A derivative according to claim 37 wherein R is CH2CH.sub.3.

41. A derivative according to claim 37 wherein R is
(CH2)8CH.sub.3.

42. A derivative according to claim 37 wherein R is
(CH2)10CH.sub.3.

Description:

FIELD OF THE INVENTION

[0001]The present invention relates to N-methylated compounds and methods
for N-demethylation of same. In particular the present invention relates
to morphine and tropane alkaloids and their derivatives and one-pot
methods for N-demethylation and N-acylation of same.

BACKGROUND OF THE INVENTION

[0002]The semisynthesis of morphine-derived antagonists, such as naloxone,
see compound 5 below, and naltrexone see compound 6 below, and other
medicinally significant compounds, from opium-derived natural products
traditionally involves standard procedures for demethylation followed by
subsequent procedures such as oxidative procedures for the introduction
of a C-14 hydroxyl group.

##STR00001##

[0003]Most commercial procedures for the production of C-14 hydroxylated
species take advantage of Δ7-8 unsaturated species, however
compounds containing α,β-unsaturated ketones have recently
been identified as potential genotoxins because of their Michael acceptor
character, and therefore it is desirable to find new routes to the
oxygenated derivatives to avoid these intermediates.

[0004]Therefore any method that avoids these standard procedures may hold
immense commercial potential for the production of morphine-derived
antagonists, such as naloxone 5, naltrexone 6, and other medicinally
significant compounds.

[0005]The development of a mild catalytic protocol for N-demethylation and
acylation of ring-C saturated morphinans would simplify strategies toward
C-14 oxygenated derivatives via potential use of an intramolecular
process by tethered functionalisation anchored at the nitrogen atom.

[0006]Current methods for N-demethylation and/or N-acylation of morphine
alkaloids are time consuming, expensive and hazardous. Thus there was an
unmet need for improved methods. Furthermore, there is an increasing
demand that production methods be environmentally friendly.

SUMMARY OF THE INVENTION

[0007]An investigation of the chemistry of morphine alkaloids and their
derivatives, such as hydrocodone, 3, and oxycodone 4, led to the present
invention which addresses the need for new methods for the production of
morphine derivatives. The invention elucidates conditions for a one-pot
oxidative N-demethylation and subsequent N-acylation of morphine
alkaloids that is cost effective and safe.

[0008]The present invention provides a one-pot method for N-demethylation
and subsequent acylation or carboxylation of N-methylated compounds,
particularly morphine alkaloids and their derivatives or tropane
alkaloids and their derivatives.

[0016]In yet another aspect of the present invention there is provided a
one-pot method for N-demethylation and subsequent carboxylation of
morphine or tropane alkaloids and their derivatives to the corresponding
carbonates. The acylating agent is preferably a dicarbamic anhydride such
as N,N'-dimethylcarbamic anhydride, N,N'-diethylcarbamic anhydride,
diphenylcarbamic acid anhydride, N,N'-diphenylcarbonic acid anhydride,
N,N'-diphenyidicarbonic diamide, N,N'-(oxydicarbonyl)bisglycine
dimethylester, pyrrole-1-carboxylic anhydride and mixtures thereof.

[0018]In one preferred embodiment, the method comprises the steps of
treating the N-methylated compound with palladium, at least one anhydride
but without any added solvent. In a preferred embodiment the palladium
source is one of Pd(OAc)2 or PdCl2 and the anhydride is acetic
anhydride. In a more preferred embodiment the palladium source is
Pd(OAc)2.

[0019]In another embodiment, the method comprises the steps of treating
the N-methylated compound with a catalyst, at least one solvent and at
least one dicarbonate. The solvent is typically benzene, dioxane, toluene
or methanol. In a preferred embodiment the catalyst is Pd(OAc)2, the
solvent is dioxane and the dicarbonate is dimethyldicarbonate.

BRIEF DESCRIPTION OF THE DRAWINGS

[0020]These and other features of the invention will become more apparent
from the following description in which reference is made to the appended
drawings wherein:

[0022]As used herein, the term "acylation" and the related term "acylating
agent" are used in the broadest sense to encompass any reaction in which
an acyl group is added to a compound. This includes reactions in which
the acyl group is derived from carboxylic acid. It also includes, for
example, the addition of an acetyl group. Types of acylating agents that
may be used in the present invention include, but are not limited to,
anhydrides, dicarbonates, dicarbamic agents and other known acylating
agents.

[0024]In particular the invention provides a method for catalysed
N-demethylation and/or N-acylation wherein the N-methylated heterocycle
is a morphine alkaloid or a derivative thereof or a tropane alkaloid or
derivative thereof.

[0037]A preferred catalyst for use in the invention is a Pd catalyst, such
as Pd, PdCl2, Pd(OAc)2, Pd(PPh3)4 and Pd(dba)2.
In a preferred embodiment the palladium catalyst is Pd(OAc)2.

[0038]The amount of catalytic palladium is preferably in the range of
about 0.01 equivalents to 1.2 equivalents. Preferably the amount of
catalytic palladium is in the range of about 0.2 equivalents to 0.5
equivalents. More preferably the amount of catalytic palladium is about
0.2 equivalents.

[0039]The methods/reactions of the invention may optionally include the
addition of a solvent such as water, benzene, dioxane, toluene,
acetonitrile and C1-C4 alcohols or a mixture of any of these. In a
preferred embodiment the solvent is dioxane. The amount of solvent added
is usually in the range of about 0.1-100 mL/gram of alkaloid.

[0040]In one exemplary aspect of the invention, hydrocodone, identified in
Scheme 1 below as 3, was treated with catalytic Pd(OAc)2 in the
presence of Ac2O, and N-acetyl norhydrocodone 7 was isolated. The
X-ray crystal structure of this novel morphine analogue is represented in
FIG. 1.

##STR00006##

[0041]In another exemplary aspect of the invention, hydrocodone,
identified in Scheme I above as 3, was treated with catalytic
Pd(OAc)2 in the presence of dimethyldicarbonate. This resulted in
the production of N-methoxycarbonyl norhydrocodone 8.

[0042]The initial experiments using stoichiometric amounts of palladium
demonstrated that benzene was an effective solvent. Further studies
indicated that dioxane was a preferred solvent. Successive reduction of
the catalyst loading to about 0.2 equivalents gave excellent results.

[0043]An interesting observation common to all conditions (described in
greater detail in Examples 1a-j below) was the isolation of two isomers
(7a, 7b) in a ratio of 3:1 in favour of the natural series.

##STR00007##

[0044]Based on the success of the N-demethylation-acylation procedure, the
reactivity of a series of anhydrides was explored. This resulted in the
isolation of a novel range of N-acylated hydrocodone derivatives as
described further in Example 2.

[0045]The utility of the invention was further demonstrated using other
N-methylated heterocycles including tropane and its derivatives. The
compatibility of the method to a range of functional groups such as
ketones and esters was also demonstrated as shown in Example 3 below.

[0046]The above disclosure generally describes the present invention. It
is believed that one of ordinary skill in the art can, using the
preceding description, make and use the compositions and practice the
methods of the present invention. A more complete understanding can be
obtained by reference to the following specific examples. These examples
are described solely to illustrate preferred embodiments of the present
invention and are not intended to limit the scope of the invention.
Changes in form and substitution of equivalents are contemplated as
circumstances may suggest or render expedient. Other generic
configurations will be apparent to one skilled in the art. All journal
articles and other documents such as patents or patent applications
referred to herein are hereby incorporated by reference.

EXAMPLES

[0047]Although specific terms have been used in these examples, such terms
are intended in a descriptive sense and not for purposes of limitation.
Methods of chemistry referred to but not explicitly described in the
disclosure and these examples are reported in the scientific literature
and are well known to those skilled in the art. A list of references is
appended and these references are hereby incorporated by reference.

Example 1

General Procedure for Demethylation/Acylation

[0048]Tertiary amine (0.1 mmol, 1.0 eq.) was dissolved in acetic anhydride
(1 ml) and Pd(OAc)2 (0.01 mmol, 0.1 eq.) added. The reaction was
heated at 80° C. for 15 hours, cooled to room temperature and
passed through a plug of silica using CHCl3:MeOH:NH4OH 80:20:1
as eluent. The volatiles were removed in-vacuo, and the residue suspended
in NaHCO3. The aqueous phase was extracted with CHCl3, and the
combined organic extracts washed with 1M HCl and brine before being dried
over magnesium sulphate, filtered and the volatiles removed in-vacuo to
yield the acyl product.

[0049]It will be understood by a person skilled in the art that the above
description for Example 1 is provided for the general procedure. The
examples shown below in Examples 1a-1j follow the general procedure
outlined above, and shown in Scheme I from compound 3 to 7, but include
the use of different sources of palladium and different amounts of
Pd(OAc)2, where applicable, and the use of different solvents, as
indicated in the table below.

[0070]Hydrocodone bitartrate (100 mg, 0.22 mmol, 1 eq.) was suspended in a
mixture of benzene and dimethyldicarbonate; 1:1 (2 ml) and Pd(OAc)2
was added. The reaction mixture was heated to 80° C. for 18 hrs,
before it was cooled to rt and filtered through a plug of celite. The
solvent was evaporated and the residue was taken up in CHCl3 and the
organic layer was washed with 1N HCl. The organic layer was dried over
MgSO4, the solvent was evaporated and the residue was purified by
flash column chromatography (CHCl3: MeOH; 100:0→90:10) to
give 25 mg of compound 8 as a mixture of 2 isomers in a ratio of 6:4
(33%) as colorless oil.

[0074]One or more currently preferred embodiments have been described by
way of example. It will be apparent to persons skilled in the art that a
number of variations and modifications can be made without departing from
the scope of the invention as defined in the claims.